In recent years solid phase organic synthesis has emerged as a powerful tool in high throughput synthesis to generate small molecular libraries for drug discovery process (for recent reviews on solid phase organic synthesis, see: (a) Balkenhohl, F.; von dem Bussche-Hunnefeld; Lansky, A.; Zechel, C. Angew. Chem. Int. Ed. Engl. 1996, 35, 2288. (b) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555. (c) Fruchtel, J. S.; Jung, G. Angew. Chem. Int. Ed. Engl. 1996 35, 17. (d) Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron 1996m 52, 4527. (e) Special issue, Acc. Chem. Res. 1996, 29). The chance of finding active lead compounds in a library depends on not only the molecular diversity, but also the key pharmacophoric heterocyclic templates. Examples of heterocyclic templates which have been reported include benzodiazepines ((a) Ellman, J. A.; Plunkett, M. J. J. Am. Chem. Soc. 1995, 117, 3306-3307), pyrrolidines ((b) Murphy, M. M.; Schullek, J. R.; Gordon, E. M.; Gallop, M. A. J. Am. Chem. Soc. 1995, 117, 7029-7030), beta-lactams ((c) Ruhland, B.; Bhandari, A.; Gordon, E. M.; Gallop, M. A. J. Am. Chem. Soc. 1995, 117, 253-254), and 4-thiazolidinediones ((d) Patek, M.; Drake, B.; Lebl, M. Tetrahedron Lett. 1995, 36, 2227-2230).
Another example of a heterocyclic template is the quinazoline-2,4-dione system. The quinazoline-2, 4-dione template appears in a wide range of bioactive molecules, including adrenergic, serotoncrgic, dopaminergic, endothelin ETA receptor ligands, and inhibitors of cyclooxygenase, collagenase, aldose reductase, and carbonic anhydrase (for recent examples, see: (a) Russo, J Med. Chem. 1991, 34, 1850. (b) Fry, D. W.; Kraker, A. J.; McMichael, A.; Ambroso, L. A.; Nelson, J. M.; Leopold, W. R.; Conners, R. W.; Bridges, A. J. Science 1994, 265, 1093-1095. (c) Zgombick, 1995, Eur. J Pharmacol. Mol. Pharmacol. Sect. 1995, 291, 9. (d) Kotani, T.; Nagaki, Y.; Ishii, A.; Konishi, Y. J Med. Chem. 1997, 40, 684-694).
Classical techniques of organic synthesis have generally entailed the use of solution-phase reactions for the preparation of organic compounds of interest. However, purification of organic molecules after solution-phase synthesis can be a tedious and sometimes expensive process, which can result in slow throughput and decreased yields of desired compounds. The poor solubility of certain heterocyclic compounds can additionally complicate synthesis of these compounds. Solid-phase synthesis (SPS) on a solid or insoluble support is an approach which can obviate some purification-related problems of solutions-phase synthesis is synthesis.
For example, there have been several recent reports of solid phase synthesis of quinazoline-2, 4-diones. One of the first methods was described by Buckman and Mohan, using a special linker prepared by multiple step synthesis and the phthalic half-ester to generate the bicyclic structure (Buckman, B. O.; Mohan, R. Tetrahedron Lett. 1996, 37, 4439-4442). Another method, reported by Smith and Gouilleux separately, involved the thermal cyclization through urethane protected anthranilamide (Smith, A.; Thomson, C. G.; Leeson, P. D. Bioorg. Med. Chem. Lett. 1996, 6, 1483; Gouilleux, L.; Fehrentz, J. A.; Winternitz, F.; Martinez, J. Tetrahedron Lett. 1996, 37, 7031-7034). Another reported method uses tetramethylguanidine with amino acids as the linkers on the solid support (Gordeev, M. F.; Hui, H. C.; Gordon, E. M.; Patel, D. V. Tetrahedron Lett. 1997, 38, 1729-1732). All of these methods use anthranilic acids as the starting materials. However, some of these reported methods involve the use of harsh conditions (such as the use of strong bases or high temperatures), do not provide uniformly high yields, or are not generally applicable to synthesis of a wide variety of quinazoline-2,4-diones.
Hydantoins represent the basic structure of a number of CNS agents, especially in antiepileptics area, of which phenytoin is an example which is still on the market. Recently, Fosphenytoin, a hydantoin introduced by Parke-Davis, was approved by FDA as the prodrug of phenytoin. Recently, several groups have reported the synthesis of hydantoins on solid phase. DeWitt and her colleagues at Parke-Davis described the synthesis of 40 hydantoins (Proc. Natl. Acad. Sci. USA (1993), 90:6909-6913; and WO 94/08711, 1994). Other references to synthesis of hydantoins include Short, K. M. et al., Tetrahedron Lett. (1996) 37, 7489-7492; Dressman, B. A. et al., Tetrahedron Lett. (1996) 37, 937-940; Hanessian, S. et al. Tetrahedron Lett, (1996) 37, 5835-5838; and Mattews, J. et al., J. Org. Chem (1997) 62, 6090-6092. However, improved methods for synthesis of hydantoins are needed.
In one aspect, the invention provides a method for preparing a substituted or unsubstituted pyrimidine-2,4-dione, e.g., a compound having the structure: 
in which the dashed line represents an optional bond; R1 and R2 are each, independently, hydrogen, alkyl, or aryl; R3 and R4 are each, independently, hydrogen, halogen, alkyl, or aryl; or R3 and R4 are joined to form a ring having from 5 to 7 atoms in the ring moiety.
In another aspect, the invention provide a method for preparing a compound on a solid support.
In yet another aspect, the invention provides a method for preparing a solid support suitable for use in solid phase synthesis. The method includes the steps of preparing the sodium alkoxide of short-chain linear polyethylene glycol by reacting the short-chain linear polyethylene glycol with sodium hydride; and reacting the sodium alkoxide of short-chain linear polyethylene glycol with chloromethylpolystyrene, such that a graft copolymer is prepared.
These and other objects, features, and advantages of the invention will be apparent from the following description and claims.